Prognostic significance of glucose‐lipid metabolic index in pancreatic cancer patients with diabetes mellitus

Abstract Background The incidence of pancreatic cancer (PC) is higher in diabetic patients due to disturbances in glucose and lipid metabolism caused by insulin resistance (IR). However, the effect of diabetes as well as IR on the prognosis of PC patients remains inconclusive. Our study aims to assess the impact of IR on the prognosis of PC patients with diabetes. Methods We conducted a retrospective analysis of 172 PC patients with diabetes in our institute from 2015 to 2021. Prognostic assessment was performed using univariate/multifactorial analysis and survival analysis. The predictive efficacy of metabolic indices was compared using receiver operator characteristic (ROC) curve analysis. Results One hundred twenty‐one of 172 patients died during follow‐up, with a median follow‐up of 477 days and a median overall survival (OS) of 270 days. Survival analysis showed a significant difference in OS by IR related parameters, which were triglyceride‐glucose index (TyG), triglyceride‐glucose index‐body mass index (TyG‐BMI), and triglyceride/high‐density lipoprotein cholesterol ratio (TG/HDL‐c). The ROC curve indicated that TyG, TyG‐BMI, and TG/HDL‐c had prognostic efficacy for PC with diabetes. We next optimized TyG‐BMI and obtained a new parameter, namely glucose‐lipid metabolism index (GLMI), and the patients were classified into GLMI low group and high group based on the calculated cutoff value. The GLMI high group had higher TyG, TyG‐BMI, TyG/HDL‐c, BMI, TG, total cholesterol (TC), TC/HDL‐c, fasting plasma glucose, CA199, and more advanced tumor stage compared to low group. Univariate and multivariate analyses showed that GLMI was an independent prognostic factor. Furthermore, the patients of GLMI high group had worse OS compared to low group and the ROC curves showed GLMI had better predictive ability than TyG and TyG‐BMI. Conclusions IR is associated with the outcome of PC patients with diabetes and higher level of IR indicates worse prognosis. GLMI has a good predictive value for PC with diabetes.

Pancreatic cancer (PC) is one of the deadliest cancers because of the difficulties in early detection and treatment.PC's prognosis remains discouraging with a 5-year relative survival rate of only 5%; and, it is predicted to become the second leading cause of cancer-related fatalities. 1,2lthough efforts were made by clinicians and researchers, there has been little significant improvement in early diagnosis and survival of PC in recent decades. 3Therefore, investigation of biological and clinical features, as well as biomarkers for PC are very important for discovery of better treating strategy.
There is growing evidence that diabetes is a high risk factor for PC incidence, [3][4][5][6] and patients with diabetes have a 1.5to 2-fold increased risk of developing PC. 7 Nevertheless, the impact of diabetes on the prognosis of PC remains uncertain.[10][11][12][13] These results emphasize PC patients with diabetes is a special population with high risk.We previously found fasting blood glucose and inflammation factors were risk factor for PC patients with diabetes (in publication process).Diabetes mellitus is a metabolic disorder and has the characteristics of decreased insulin secretion and/or insulin resistance (IR). 1,14According to existed researches, IR increases the risk of various types of cancer, such as prostate cancer, 15 non-small cell lung cancer, 16 gastric cancer, 17 and obesity-related cancers. 18And it is also associated with a higher mortality rate. 19However, it remains unclear whether IR is correlated with patients' prognosis for PC patients with diabetes.
In this study, we aim at evaluating the predictive value of IR in the prognosis of PC patients with diabetes mellitus by analyzing triglyceride-glucose index (TyG), triglyceride/high-density lipoprotein cholesterol ratio (TG/ HDL-c), and triglyceride-glucose index-body mass index (TyG-BMI), which were simple measures of IR. [20][21][22][23][24][25] We also develop a modified index, which is glucose-lipid metabolism index (GLMI) and test its predictive ability in PC patients with diabetes mellitus.were: (1) Preliminary imaging diagnosis and pathological examination of PC, and (2) presence of diabetes mellitus or impaired glucose tolerance (IGT).The diagnostic criteria for diabetes mellitus in this study were: fasting plasma glucose (FPG) level of ≥7.0 mmol/L.Additionally, diagnostic criteria for diabetes mellitus included a 75 g oral glucose tolerance test (OGTT) with 2 h FPG level of ≥11.1 mmol/L, or glycated hemoglobin >6.5%, or previous diagnosis of diabetes or use of hypoglycemic agents.Criteria for IGT were a 75 g OGTT with 2-h FPG level ≥7.8 mmol/L. 26The exclusion criteria were: These included incomplete clinical and pathological data and the presence of combined other tumors.A total of 172 PC patients with diabetes mellitus were included in the followup analysis.The Ethics Committee of the Guangdong Academy of Medical Sciences approved this study.

| Clinical information
Demographic, serologic, radiologic, and pathologic information was collected from eligible patients.Such as age, sex, body mass index (BMI), triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), TC/HDL-c, FPG, hemoglobin (HB), total bilirubin (TBIL), alanine aminotransferase (ALT), γglutamyl transpeptidase (γ-GGT), albumin (ALB), activated partial thromboplastin time (APTT), CA125, CEA, CA19-9, treatment and TNM staging.TNM staging was performed according to the 8th edition of the AJCC PC staging system.Based on the above indicators, TyG, TyG-BMI, TG/HDL-c and GLMI were calculated, respectively, and the calculation methods were as follows 27,28 : All patients who were enrolled underwent an outpatient and telephone follow-up along with a review of their medical history.The primary endpoint was the OS, which was defined as the duration between diagnosis and either death or the last follow-up.The last follow-up was accomplished on July 31, 2022.

| Statistical methods
The statistical analysis was performed using SPSS 27.0 software.The clinicopathological data of the patients were presented as mean ± standard deviation for continuous variables and frequency (percentage) for categorical variables.
For continuous variables, independent samples t-test was carried out whereas for categorical variables, chi-squared test/Fisher exact test was performed.COX proportional hazards regression analysis was conducted to evaluate the univariate and multivariate survival risk.Kaplan-Meier analysis (log-rank test) was utilized to plot the survival curves, and to determine the optimal survival-related cutoff value for GLMI.Furthermore, the predictive efficacy of each metabolic index was compared using time-dependent receiver operator characteristic (ROC) curve analysis to calculate the area under the curve (AUC).p < 0.05 (two-tailed) differences were considered statistically significant.

| RESULTS
The study included 172 PC patients with diabetes mellitus, who were ultimately followed for a median of 477 days.Out of these, 121 patients died within the follow-up period with a median survival of 270 days.

| GLMI, a new parameter, is associated with IR and tumor stage in PC patients with diabetes mellitus
In order to achieve a superior predictive value, we optimized TyG-BMI and obtained GLMI (GLMI = TyG × BMI × TC/ HDL-c).Using Kaplan-Meier survival curves, the optimal cutoff value for the GLMI was calculated to be 222.779.Based on this cutoff value, patients were classified into two groups: a low IR score group (low group) and a high IR score group (high group).GLMI scores ≤222.779 were used as the low group, which had 94 cases (54.7%), and GLMI scores >222.779 were used as the high group, which had 78 cases (45.3%).The high group had significantly higher TyG, TyG-BMI, TyG/HDL-c, BMI, TG, TC, TC/HDL-c, FPG, HDL-c, CA199, HB, ALB, TBIL, and more advanced TNM stage compared to the low group.In stage I and II, the number of patients in the GLMI high group was significantly lower than that in the low group (33 vs. 56 patients); however, in stage III and IV, the number of patients in the GLMI high group was significantly higher than that in the low group (45 vs. 38 patients).The statistical difference was significant (p < 0.05).No statistically significant differences were observed in age, gender, treatment, location, CEA, CA125, γ-GGT, ALT, and APTT between the groups (p > 0.05) (Table 1).These indicate higher GLMI is associated with IR and advanced tumor stage in PC patients with diabetes mellitus.

| DISCUSSION
Diabetes is associated with increased incidence of PC.As economic levels have risen and dietary structures have changed, the prevalence of diabetes mellitus has gradually increased, alongside increased incidence of PC. 29,30 In 50%-80% of PC patients, diabetes mellitus is comorbid, 31,32 and approximately 85% have IGT. 3334,35 Some studies found diabetes led to worse survival compared to non-diabetes PC patients.Indeed, hyperglycemia may promote malignant phenotype of cancer cells.For example, hyperglycemia fosters tumor cell growth by creating a nutrient-rich environment and by promoting the resistance of PC cells to gemcitabine through the regulation of the ROS/MMP-3 signaling pathway. 36Moreover, hyperglycemia fuels the proliferation of PC cells through the induction of EGF expression and EGFR activation. 37In contrast, a few studies found comparable prognosis between PC patients with or without diabetes.The different results may be attributed to the different glucose controlling level or administration of anti-hyperglycemic medications like metformin. 38urther studies are needed to investigate the influence of glucose controlling level and oral hypoglycemic drugs on cancer-related outcome.Insulin resistance plays a crucial role in the pathophysiology of diabetes mellitus and causes a variety of metabolic disorders such as hyperglycemia, hyperinsulinemia, dyslipidemia and visceral obesity. 16,26,28,39,40Currently, the homeostatic model assessment of IR and the hyperinsulinemic euglycemic clamp are accurate methods for assessing IR.However, due to their complexity, high cost of operation, and lack of a standardized method for insulin determination, these two methods are not favorable for clinical promotion. 27,28,4128]41 The time-dependent ROC curves demonstrated that TyG (AUC = 0.616), TG/HDL-c (AUC = 0.674), and TyG-BMI (AUC = 0.633) all had predictive value for the prognosis of PC patients with diabetes mellitus.Other studies also found IR occurred in 85%-95% of all diabetic patients 30,42 and was associated with the aggressiveness of pancreatic ductal adenocarcinoma. 43Research has shown that diabetic patients face a higher risk of cancer recurrence and cancer-related death. 11Mechanistically, high insulin levels can promote the proliferation and differentiation of PC cells and angiogenesis through the activation of the insulin and insulin-like growth factor axis 44 and the PI3K/Akt and MAPK signaling pathways, 30,42 leading to PC progression.In addition, IR can induce hyperglycemia, hyperinsulinemia, and dyslipidemia, which may promote PC cells to remodel their metabolic phenotypes and increase their aggressiveness. 1,45Combining these with our findings, we believe that IR is a critical parameter which affects outcome of PC patients with diabetes.The predictive efficacy of TG/HDL-c (AUC = 0.674) was found to be superior to that of TyG (AUC = 0.616) and TyG-BMI (AUC = 0.633), as depicted in Figure 2. Contrary to our findings, in studies of benign diseases, TyG-BMI and TyG showed superior efficacy in evaluating IR than TG/ HDL-c. 27,28We speculated that cholesterol metabolism may affect the progression of PC, as IR results in elevated triglyceride levels and decreased HDL-c levels. 46And cholesterol metabolism is connected to all stages of tumors, including tumorigenesis, tumor resistance, and immune escape.8][49] Therefore, with reference to the optimization of TyG-neck circumference (TyG-NC), TyG-neck circumference to height ratio (TyG-NHtR), TyG-waist circumference (TyG-WC), TyG-waist to height ratio (TyG-WHtR), TyG-body mass index (TyG-BMI), 22 we optimized TyG-BMI, and the product of TyG-BMI and TC/HDL-c was used as the GLMI.The level of IR in PC patients with diabetes was evaluated using GLMI.The Kaplan-Meier survival curves demonstrated that patients with a high GLMI score had a median OS of 162 days while the low score group had 420 days (p < 0.001).Our analysis revealed that GLMI was an independent prognostic factor for PC patients with diabetes mellitus, confirmed by both univariate and multivariate COX regression analysis (p < 0.001, Table 2).Regarding the prognosis of PC patients with diabetes mellitus, GLMI (AUC = 0.721) demonstrated greater efficacy in predicting prognostics than TyG, TG/HDL-c, and TyG-BMI.It will be interested to investigate the association between GLMI and blood glucose level, IR and outcomes of PC patients with diabetes in large-scale, prospective studies.
In summary, we found IR was an unfavorable factors for PC patients with diabetes mellitus.GLMI, a simple and practical indicator, may reflect the degree of IR and have a good predictive value for the prognosis of PC patients with diabetes mellitus.
F I G U R E 3 K-M curves for overall survival by different GLMI level and receiver operator characteristic curves for GLMI.GLMI, glucose-lipid metabolism index.

| Limitations of this study
This study is a single-center retrospective study with a relatively limited sample size, which may lead to a certain selection bias and a class I error.Moreover, the study includes PC patients with various pathological types, resulting in a certain degree of heterogeneity.Additionally, diabetes mellitus plays a multifaceted role in PC, and this study only examines IR as a manifestation of diabetes mellitus, which is not comprehensive enough.

F
I G U R E 2 K-M curves for overall survival by different IR indexes and receiver operator characteristic curves for different IR indexes.IR, insulin resistance.
Baseline data from 172 pancreatic cancer patients with diabetes mellitus with varying degrees of insulin resistance.
Univariate and multivariate analysis of overall survival in 172 patients with pancreatic cancer and diabetes.
T A B L E 2